Stress Programming

Question 1

Stress regulation divided into 2 parts…

Answer 1

1) Sympatho-adreno medullary axis (ANS, immediate but short lived responses - fight or flight (BP, HR))
2) HPA axis (hypothalamic pituitary adrenocortical axis) - slower but longer lasting responses e.g. increased glucocorticoids

Question 2

HPA axis

Answer 2

• PVN of the hypothalamus contains neurons producing CRH and AVP; project to median eminence & release into pituitary portal system.
• Pituitary gland then releases ACTH (adrenocorticotropic hormone)
• Adrenal glands release glucocorticoids (cortisol/corticosterone) and catecholamines (adrenaline, NA)
• Negative feedback to brain via glucocorticoid receptors (GR) and mineralcorticoid receptors (MR)

More GRs in the CNS –> better suppression of CRH and therefore lower stress response.
Excess glucocorticoids in stress response –> necrosis, ageing, morphological changes etc. which affect learning and memory.

Question 3

Study on maternal behaviour

Answer 3

Rat behaviours: LG and ABN
2 groups: 1 SD above and 1 SD below the mean for these behaviours.
Pups had no difference in basal levels of stress hormones but did when put under stress (lower plasma ACTH and corticosterone responses)
In the PVN, mRNA expression showed CRH was lower and GR higher.

Adults reared by good mothers also performed better in Morris water maze. Synaptic marker proteins (synaptophysin and NCAM) showed increased hippocampal synaptogenesis or synaptic survival.

Good mothers –> CALMER and SMARTER offspring

Question 4

Non-genomic behavioural transmission

Answer 4

Same rat study showed when pups grew up, their maternal behaviours mirrored their mothers. Pups of “bad” mothers also spent less time exploring novel objects (anxiety).

Cross fostering studies not as expected: foster mother being good or bad –> both pups and low anxiety - genetic and environmental affects?

Question 5

Epigenetics of the good/bad rat mothers

Answer 5

Good mothers had high hippocampal serotonin. Binding within the hippocampus –> intracellular cascade, in which a TF called NGFiA binds to a glucocorticoid receptor, Nr3c1.

In pups of bad mothers, high levels of methylation in GR promoter –> repression, NGFiA can’t bind.

Question 6

Human data for epigenetics (3)

Answer 6

Suicide victims: looked at brains of childhood trauma/abuse victims vs not. Abuse –> lower GR expression in hippocampus and higher GR methylation.

Holocaust survivor offspring: higher risk of anxiety and depressive disorders, higher risk of PTSD (especially if mother experienced PTSD). Maternal age during holocaust influences this (adult more likely).

9/11: high levels of maternal PTSD/depression following exposure to 9/11 either directly or indirectly –> increased prenatal deaths (particularly in males), increased behavioural problems in preschool.

Question 7

Why do stress-related disorders only develop in some? (3)

Answer 7

Cumulative stress hypothesis: more stress in early life plus stress later on –> increased risk of stress-related disorders

Mismatch hypothesis: no early life stress plus stress later on –> increased risk (early stress “primes” you)

3D model: “programming sensitivity” depends on 1) environment (type/level of stress), 2) genetic background and 3) individual (age, gender).

Question 8

MAOA

Answer 8

Breaks down a number of transmitters including dopamine, serotonin, NA.
MAOA KO mice –> aggression
Polymorphisms in the promoter can increase or decrease activity.
Study grouped children based on severity of maltreatment (none, probable, severe). Low MAOA activity allele –> increased risk of antisocial behaviour. Maltreatment didn’t increase risk of antisocial behaviour if they had high activity allele.

Question 9

PTSD only develops in 15% of traumas.. Why?

Answer 9

Originally thought that trauma –> chronic stress –> increased glucocorticoids –> hippocampal damage –> decreased size.
BUT twin studies showed that low hippocampal volume is actually a predisposing factor to PTSD rather than a consequence.